We are interested in gene regulation in the immune system. Our emphasis is to study the function of three proteins that bind to the regulatory region of MHC class I and other genes. These proteins, (1) RXRbeta, (2) ICSBP), and (3) UCRBP were previously isolated in this laboratory. They belong to distinct DNA binding protein families and have characteristic domain structures. By transfection studies, we have shown that all three proteins affect transcription of reporter genes driven b specific target elements: RXRbeta activates retinoic acid dependent transcription of MHC class I reporters through a positive regulatory element. ICSBP represses transcription of MHC class I and many other genes that are regulated by interferons. UCRBP shows a dual activity in that it either stimulates or represses transcription of a UCR-driven promotor, depending on the amount of UCRBP transfected into the cell. Studying recombinant proteins we have learned that RXRbeta and ICSBP act in association with another protein. The most striking finding has come from the analysis of RXRbeta: RXRbeta heterodimerizes with multiple nuclear hormone receptors, that as such confers the ability to bind to a target DNA at a high affinity. Studies of RXRbeta led us to propose that RXRbeta introduces a combinatorial mechanism into receptor-mediated gene regulation, thereby increasing the repertoire and versatility of their action. ICSBP also interacts with a cytoplasmic protein that translocates to the nucleus upon interferon treatment, which again confers high affinity binding to the target. These results indicate that a specific protein-protein interaction is an integral mechanism of the action of these DNA binding proteins.